Comprehensive analysis of TLR4-induced transcriptional responses in interleukin 4-primed mouse macrophages

Immunobiology. Sep-Oct 2010;215(9-10):780-7. doi: 10.1016/j.imbio.2010.05.032. Epub 2010 Jun 4.

Abstract

Interferon (IFN)gamma and interleukin (IL)-4 are central regulators of T helper 1 (Th1) and T helper 2 (Th2) immune responses, respectively. Both cytokines have a major impact on macrophage phenotypes: IFNgamma-priming and subsequent TLR4 activation induces so-called "classically activated" macrophages that are characterized by pronounced pro-inflammatory responses, whereas IL-4-treated macrophages, commonly called "alternatively activated", are known to develop enhanced capacity for endocytosis, antigen presentation and tissue repair and are generally considered anti-inflammatory. Considering IL-4 as priming rather than activating stimulus, we now compared the TLR4-dependent global gene activation program in IFNgamma- versus IL-4-pretreated mouse macrophages, which has rarely been studied so far. Although both cytokines frequently induced opposing effects on gene transcription, the subsequent activation of bone marrow-derived macrophages by lipopolysaccharide (LPS) produced a strong, priming-dependent pro-inflammatory response in both macrophage types. For example, the production of key pro-inflammatory cytokines IL-6 and IL-12 was significantly higher in IL-4- versus IFNgamma-primed macrophages and several cytokine genes, including Il19, Ccl17, Ccl22, Ccl24 and Cxcl5, were preferentially induced in "alternatively" primed and LPS activated mouse macrophages. In a subset of genes, including IL12a, IFNgamma-priming was actually found to suppress LPS-induced gene expression in a Stat1-dependent manner. Our data suggest that IL-4-priming is not per se anti-inflammatory but generates a macrophage that is "tissue protective" but still capable of mounting a strong inflammatory response after TLR4-dependent activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigen Presentation
  • Cells, Cultured
  • Endocytosis / immunology
  • Gene Expression Profiling
  • Immunization
  • Inflammation
  • Interferon-gamma / immunology
  • Interferon-gamma / metabolism*
  • Interleukin-4 / immunology
  • Interleukin-4 / metabolism*
  • Lipopolysaccharides / immunology
  • Lipopolysaccharides / metabolism
  • Macrophages / immunology
  • Macrophages / metabolism*
  • Macrophages / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • STAT1 Transcription Factor / genetics
  • Th1-Th2 Balance
  • Toll-Like Receptor 4 / metabolism*
  • Transcriptional Activation / immunology*

Substances

  • Lipopolysaccharides
  • STAT1 Transcription Factor
  • Toll-Like Receptor 4
  • Interleukin-4
  • Interferon-gamma